ABSTRACT It has been suggested that neuronal hyperexcitability is an important characteristic in Alzheimer?s disease (AD) because it contributes to the impairment in memory and increasing levels of amyloid ? (A?)?that characterize the disease. Using animal models of AD neuropathology we suggest that the most common form of hyperexcitability is a synchronized spike in hippocampus and cortical neurons that is similar to the spikes between seizures in epilepsy, called interictal spikes (IIS). Our data suggests that IIS occur very early and are very common, yet seizures are rare. Therefore we have a potential opportunity to characterize a novel biomarker, IIS, and clarify the relationship between hyperexcitability and AD. Preliminary data have primarily used a mouse model where the precursor to amyloid precursor protein (APP), the precursor to A? is mutated to simulate a Swedish family with familial AD, and expressed widely in the brain. By 5 weeks of age, months before A? deposition, we have found IIS as the animals are sleeping. With age the animals develop frequent IIS that occur in other brain states besides sleep and there are also memory impairments and plaque formation. In other animal models IIS also occur, yet seizures are rare. When examining the brains of the young mice we find that the basal forebrain (BF) cholinergic neurons and dentate gyrus granule cells show signs of elevated activity, instead of hypoactivity that characterizes the brain at older ages. We suggest that BF cholinergic neurons stimulate the granule cells and this leads to synchronized action potentials. In support, the muscarinic cholinergic antagonist atropine reduces the IIS in sleep, as well as in vitro measurements in hippocampal slices that we think reflect the abnormal activity. We now propose experiments to test these hypotheses with multiple methods including viral-mediated silencing of cholinergic neurons in vivo. In the last part of the proposal we will examine two strategies that our pilot experiments show can reduce IIS to determine if cognition and neuropathology are ameliorated. One of these has already been tested in a mouse model of Down?s syndrome, a condition where AD is prevalent: maternal choline supplementation. The second, a reduction of the neurotrophin receptor p75 (p75NTR), has been tested in one of the mouse models we will use, the Tg2576 mouse, and it is already known that it ameliorates memory impairments in the mice. In summary, this project will address an area of AD research which has been difficult to clarify and controversial: hyperexcitability in AD. We suggest that there are early signs of hyperexcitability, IIS, that present opportunities for better mechanistic understanding and intervention.